Certain pharmaceutically useful oxadiazoles

ABSTRACT

Novel compounds of formula (I), processes for their preparation, and their use as pharmaceutical agents are described: ##STR1## in which X represents a group ##STR2## wherein one of Y and Z represents nitrogen and the other represents CR where R is selected from halogen, CN, OR 1 , SR 1 , N(R 1 ) 2 , NHR 1 , NHCOR 1 , NHCOOCH 3 , NHCOOC 2  H 5 , NHOR 1 , NHNH 2 , COR 1 , COR 2 , C 2-4  alkenyl, C 2-4  alkynyl or C 1-2  alkyl substituted with OR 1 , N(R 1 ) 2 , SR 1 , CO 2  R 1 , CON(R 1 ) 2  or one or two halogen atoms, in which R 1  is hydrogen or C 1-2  alkyl and R 2  is OR 1 , NH 2  or NHR 1  ; and each of p and q independently represents an integer of 2 to 4.

This invention relates to compounds having pharmaceutical activity, to aprocess for their preparation and their use as pharmaceuticals. EP-A No.0239309 (Merck Sharp and Dohme Ltd.) discloses substituted oxadiazoleswhich are muscarinic agonists. A novel group of compounds has now beendiscovered which also enhance acetylcholine function via an action atmuscarinic receptors within the central nervous system and are thereforeof potential use in the treatment and/or prophylaxis of dementia inmammals. According to the present invention, there is provided acompound of formula (I) or a pharmaceutically acceptable salt thereof:##STR3## in which X represents a group ##STR4## wherein one of Y and Zrepresents nitrogen and the other represents CR where R is selected fromhalogen, CN, OR¹, SR¹, N(R¹)₂, NHR¹, NHCOOCH₃, NHCOOC₂ H₅, NHOR¹, NHNH₂,COR¹, COR², C₂₋₄ alkenyl, C₂₋₄ alkynyl or C₁₋₂ alkyl substituted withOR¹, N(R¹)₂, SR¹, CO₂ R¹, CON(R¹)₂ or one or two halogen atoms, in whichR¹ is hydrogen or C₁₋₂ alkyl and R² is OR¹, NH₂ or NHR¹ ; and each of pand q independently represents an integer of 2 to 4.

The term halogen includes bromine, chlorine and fluorine.

Certain compounds of formula (I) are capable of existing in a number ofstereoisomeric forms including enantiomers. The invention extends toeach of these stereoisomeric forms, and to mixtures thereof (includingracemates). The different stereoisomeric forms may be separated one fromthe other by the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis.

The compounds of formula (I) can form acid addition salts with acids,such as the conventional pharmaceutically acceptable acids, for examplehydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic,citric, lactic, mandelic, tartaric, oxalic and methanesulphonic.

Preferably, p and q each independently represents 2 or 3. Mostpreferably p represents 2 and q represents 2 or 3.

Preferably, R is selected from NH₂, CH₂ F and NHCOCH₃. Suitable examplesof X include 3-fluoromethyl-1,2,4-oxadiazol-5-yl,3-amino-1,2,4-oxadiazol-5-yl and 3-acetylamino-1,2,4-oxadiazol-5-yl.

The invention also provides a process for the preparation of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, whichprocess comprises cyclising a compound of formula (II): ##STR5## inwhich (i) A represents X or a group convertible thereto and B represents--(CH₂)_(r) L₁ where L₁ is a leaving group or A and L₁ togetherrepresent --COO--; one of r, s and t is 1 and the other twoindependently represent an integer of 2 to 4, and R₁₀ representshydrogen or an N-protecting group; to give a compound of formula (IIa):##STR6## in which X' represents X or a group convertible thereto,Z.sup.⊖ is an anion and the remaining variables are as previouslydefined; or (ii) A represents an electron withdrawing group, B

represents hydrogen and R¹⁰ represents --(CH₂)_(r) L₂ where L₂ is aleaving group; one of s and t is 1 and the other and r independentlyrepresent an integer of 2 to 4; to give a compound of formula (IIb):##STR7## in which W represents an electron withdrawing group or X andthe remaining variables are as previously defined; and thereafter,optionally or as necessary, removing any R₁₀ N-protecting group,converting W to X., converting X to X, converting X to other X and/orforming a pharmaceutically acceptable salt.

The deprotection, conversion and interconversion steps may be carriedout in any appropriate order.

Examples of the leaving groups L₁ and L₂ include halo such as bromo orchloro, tosyloxy and mesyloxy.

Examples of R₁₀ when an N-protecting group include benzyl andsubstituted benzyl.

Examples of A and X. when groups convertible to X include C₁₋₄alkoxycarbonyl, benzyloxycarbonyl and cyano.

The cyclisation reaction is a nucleophilic substitution which may becarried out under conventional conditions appropriate to the groups Aand B. Thus, when B is (CH₂)_(r) B_(r) and A is C₁₋₄ alkoxycarbonyl, thecyclisation is carried out in an inert solvent such as toluene or etherat elevated temperature. When B is (CH₂)_(r) OTos or (CH₂)_(r) OMes, itis preferably obtained by treatment of a (CH₂)_(r) OH group with asuitable reagent such as tosyl chloride or mesyl chloride, in a basesuch as pyridine, whereupon the cyclisation may proceed at ambienttemperature, or at elevated temperature in an inert solvent such astoluene. When A and L₁ together represent --COO--, the cyclisation maybe carried out in a lower alkanol such as ethanol in the presence ofacid such as hydrogen bromide. In the resulting compound of formula(IIa), X will be an alkoxycarbonyl group corresponding to the loweralkanol used for the cyclisation.

Where R₁₀ is an N-protecting group such as benzyl, this may be removedby conventional hydrogenation, preferably catalytically over a suitablecatalyst such as Pd/C. Examples of A when an electron withdrawing groupinclude C₁₋₄ alkoxycarbonyl and cyano.

When A is an electron withdrawing group such as C₁₋₄ alkoxycarbonyl, Bis hydrogen and R¹⁰ is -(CH₂)_(r) L₂ where L₂ is, for example, chloro,the cyclisation may be effected by treatment of the compound of formula(II) with lithium diisopropylamide.

The conversion of W and X' may be carried out conventionally with regardto the group X.

Thus, the group X may be obtained from a W or X' group as described in,for example standard text books on heterocyclic chemistry such as`Comprehensive Heterocyclic Chemistry`, A. R. Katritzky and C. W. Rees,Pergamon, 1984.

The W or X' group is first converted, as necessary, to a suitablestarting group X" for the chosen conversion reaction to give therequired group X.

An X" carboxy group may be obtained by conventional de-esterification ofan X or W alkoxycarbonyl group. Where R¹⁰ is an N-protecting group andX' or W is a benzyloxycarbonyl group, the de-esterification anddeprotection steps may conveniently be effected simultaneously byconventional hydrogenation such as described above. Alternatively, an X'carboxy group may be obtained by conventional acid hydrolysis of an X'or W cyano group.

An X" chlorocarbonyl group may be obtained by treatment of an X" carboxygroup with thionyl chloride at elevated temperature.

When X represents 3-substituted-1,2,4-oxadiazol-5-yl, an X"chlorocarbonyl or X' carboxy ester group may be reacted with anappropriate amide oxime, at elevated temperature in an inert, polarsolvent such as chloroform, and the resulting substitution productcyclised at elevated temperature in a suitable solvent such as tolueneor xylene.

When X represents 3-amino-1,2,4-oxadiazol-5-yl, an X" chlorocarbonyl orX' carboxy ester group may be reacted with a hydroxy guanidinederivative under basic conditions.

When X represents 5-substituted-1,3,4-oxadiazol-2-yl, an X" carboxy orcarboxy ester group may be converted to the acid hydrazide byconventional procedures. For 5 example, the acid may be converted to aC₁₋₆ alkyl 6 ester e.g. methyl, with the appropriate C₁₋₆ alkanol e.g.methanol under conventional esterification conditions, and the resultingester reacted with hydrazine at elevated temperature to give the acidhydrazide. The acid hydrazide may then be acylated with an appropriateagent such as the anhydride and then cyclised by heating with phosphorusoxychloride or polyphosphoric acid, or methane sulphonic acid in thepresence of phosphorus pentoxide.

Interconversion of R within a group X may be carried out conventionally.Thus, an amino group may be acylated, converted to chloro, or to --NHNH₂via a diazonium intermediate, --N₂ ⁺. Similarly, a chloro substituentmay be converted by reaction with a nucleophile such as methoxide; andalkoxycarbonyl groups may be converted, via carboxy, to an aminosubstituent --NH₂.

Compounds of formula (II) may be prepared conventionally.

Where A is C₁₋₄ alkoxycarbonyl, B is (CH₂)_(r) L₁ and R₁₀ is hydrogen oran N-protecting group, the compound of formula (II) may be prepared bytreating a compound of formula (III): ##STR8## where R⁹ is C₁₋₄ alkyland the remaining variables are as previously defined, with lithiumdiisopropylamide, prepared in situ from diisopropylamine andn-butyllithium followed by reaction with a compound L₃ (CH₂)_(r) L₁where L₃ is a leaving group, in an inert solvent such as ether atdepressed to elevated temperature. Both L₁ and L₃ are suitably bromo.

Where A and L₁ together represent --COO-- and r is 2, the compound offormula (II) may be prepared by reacting the compound of formula (III),treated with lithium diisopropylamide as before, with ethylene oxide inan inert solvent such as ether at depressed to elevated temperature.

Where A is an electron withdrawing group such as C₁₋₄ alkoxycarbonyl, Bis hydrogen and R₁₀ is (CH₂)_(r) L₂, the compound of formula (II) may beprepared by reacting the compound of formula (III) where R₁₀ is hydrogenwith a compound L₃ (CH₂)_(r) L₂ where L₃ is as previously defined, in asolvent such as acetone in the presence of a base such as potassiumcarbonate. The leaving group L₃ is preferably bromo and L₂ is preferablychloro.

Compounds of formula (III) are known compounds or may be prepared byanalogous methods to those for preparing known compounds. The compoundof formula (III) where s is 2 and t is 1 and R₁₀ is benzyl may beprepared by the cyclisation of di-C₁₋₄ alkyl itaconate in theappropriate alkanol with benzylamine at elevated temperature, followedby reduction of the resulting oxo group at the 2-position of thepyrrolidine ring with BH₃ in tetrahydrofuran, at ambient to elevatedtemperature.

Pharmaceutically acceptable salts of the compounds of formula (I) may beformed conventionally by reaction with the appropriate acid such asdescribed above under formula (I).

The compounds of the present invention enhance acetylcholine functionvia an action at muscarinic receptors within the central nervous systemand are therefore of potential use in the treatment and/or prophylaxisof dementia.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, suppositories, reconstitutable powders, or liquidpreparations such as oral or sterile parenteral solutions orsuspensions.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

The solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, or hydrogenated edible fats; emulsifying agents, forexample lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles(which may include edible oils), for example almond oil, fractionatedcoconut oil, oily esters such as esters of glycerine, propylene glycol,or ethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid; and if desired conventional flavouringor colouring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending on the method ofadministration.

The invention also provides a method of treatment and/or prophylaxis ofdementia in mammals including humans, which comprises administering tothe sufferer an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

The dose of the compound used in the treatment of such disorders willvary in the usual way with the seriousness of the disorders, the weightof the sufferer, and the relative efficacy of the compound. However, asa general guide suitable unit doses may be 0.05 to 100 mg. for example0.2 to 50mg; and such unit doses may be administered more than once aday, for example two or three times a day, so that the total dailydosage is in the range of about 0.01 to 5 mg/kg; and such therapy mayextend for a number of weeks or months.

Within the above indicated dosage ranges no toxicological effects areindicated for the compounds of the invention.

In a further aspect the invention provides a compound of formula (I) ora pharmaceutically acceptable salt thereof for use as an activetherapeutic substance.

The invention further provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use in the treatmentand/or prophylaxis of dementia.

In another aspect the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for the treatment and/or prophylaxis ofdementia.

The following examples illustrate the invention and the followingdescriptions illustrate the preparation of intermediates thereto.

DESCRIPTION 1 Fluoroacetamide Oxime (D1) ##STR9##

A solution of sodium methoxide (prepared from 1.84g, 0.080 mole ofsodium) in methanol (40ml) was added to a solution of hydroxylaminehydrochloride (5 56g, 0.080 mole) in methanol (40ml) and the mixturestirred for 20 minutes. The mixture was filtered through a pad ofkieselguhr and the filtrate cooled to 0° C. and treated withfluoroacetonitrile (5.0g, 0.085 mole). The solution was allowed to warmup to room temperature over 1h and then concentrated in vacuo. Theresidue was treated with methanol (15ml)/chloroform (120ml), filteredand the filtrate concentrated in vacuo to give the title compound (D1)as a white solid (6.8g, 92%) m.p. 41°-43° C.

DESCRIPTION 2 (+)Ethyl 1-(2-chloroethyl)-3-piperidylcarboxylate (D2)##STR10##

A solution of ethyl 3-piperidylcarboxylate (100g, 0.64 mole) in acetone(600ml) was treated with 1-bromo-2-chloroethane (54ml, 0.64 mole) andanhydrous potassium carbonate (138g, 1.00 mole) and the mixture stirredat room temperature for 24h. The mixture was concentrated in vacuo andthe residue treated with water (400ml) and extracted with ether (2×200ml). The combined ether extracts were dried (Na₂ SO₄) and concentratedin vacuo to leave a yellow oil, which was purified by chromatography onsilica gel eluting with 50% ether/60-80 petrol to give the titlecompound (D2) as a pale yellow oil (50.0g, 36%). ¹ H Nmr (CDCl₃)δ1.25(3H, t, J=7Hz), 1.40-3.10 (11H, m), 3.58 (2H, t, J™7Hz), 4.15 (2H, q,J=7Hz)

DESCRIPTION 3 (±) Ethyl 1-azabicyclo[3.2.1]ct-5 -ylcarboxylate (D3)##STR11##

A solution of diisopropylamine (33.6ml, 0.24 mole) in dry ether (1500ml)at -65° C. under nitrogen was treated with 1.5M n-butyllithium in hexane(150ml, 0.225 mole) and the solution stirred for 15 mins, before addingN,N,N',N'-tetramethylethylenediamine (68ml, 0.45 mole). After stirringfor a further 15 mins, the solution was treated with a solution of (±)ethyl 1-(2-chloroethyl)-3-piperidylcarboxylate (D2, 44.7 g, 0.204 mole)in dry ether (100ml) and the mixture allowed to warm up to roomtemperature over 2 h. The reaction mixture was treated with potassiumcarbonate solution (300ml) and the ether layer separated, dried (Na₂SO₄) and concentrated in vacuo to leave an orange oil. This was purifiedby chromatography on silica gel eluting with 10% methanol/chloroform togive the title compound (D3) as a yellow oil (31.9g, 84%), b.p.120°-130° C.₀.4 mm (Kugelrohr apparatus). ¹ H Nmr (CDCl₃)δ1.25 (3H, t,J™7Hz), 1.10-2.20 (6H, m), 2.60-3.25 (6H, m), 4.20 (2H, q, J™7Hz)

DESCRIPTION 4 (±) Methyl 1-benzyl-2-oxo-4-pyrrolidylcarboxylate (D4)##STR12##

A solution of dimethyl itaconate (50g, 0.32mole) in methanol (40ml) wastreated with benzylamine (34.6ml, 0.32mole) and the mixture heated underreflux for 2.5 h. The solution was then concentrated in vacuo and theresidue purified by distillation (b.p. 162°-170° C./0.2 mmHg) to give apale yellow oil. This solidified on standing to give the title compound(D4) as a beige solid (66.2g, 89%), m.p. 62°-63° C.

DESCRIPTION 5 (±) Methyl 1-benzyl-3-pyrrolidylcarboxylate (D5) ##STR13##

A solution of (±) methyl 1-benzyl-2-oxo-4-pyrrolidylcarboxylate (D4,35.4g, 0.18 mole) in dry THF (135 ml) was added dropwise over 30 mins to1M borane-THF solution (228 ml, 0.23 mole) at 0° C. under nitrogen, andwhen addition was complete the solution was heated under reflux for 1h.The solution was cooled to room temperature, then treated dropwise with8% hydrogen chloride/methanol (114 ml, 0.25 mole HCl) and stirred for 18h, followed by 3 h at reflux. The mixture was then concentrated in vacuoand the residue treated with 3 water (40 ml), washed with ether (2×50ml), basified with 40% sodium hydroxide solution, saturated withpotassium carbonate and extracted with ether (3×70 ml). The combinedextracts were dried (Na₂ SO₄) and concentrated in vacuo to leave ayellow oil, which was purified by distillation (b.p. 146° C./0.7 mmHg)to give the title compound (D5) as a colourless oil (19.8g, 50%).

DESCRIPTION 6 (±) 7-Benzyl-7-aza-2-oxaspiro[4.4]nonan-1-one (D6)##STR14##

A solution of diisopropylamine (6.6 ml 0.047 mole) in dry ether (100 ml)at -65° C. under nitrogen was treated with 1.6M n-butyllithium in hexane(26.2 ml, 0.042 mole) and the solution stirred for 15 min, beforetreating with N,N,N',N'-tetramethylethylenediamine 12.3 ml). Afterstirring for a further 10 min, the solution was treated dropwise over 10min with a solution of (±) methyl 1-benzyl-3-pyrrolidylcarboxylate (D5,7.50 g, 0.034 mole) in dry ether (20 ml) and stirring continued at -65°C. for 15 min. Ethylene oxide (3.1 g, 0.070 mole) was then bubbled intothe solution over 20 min and the mixture was allowed to warm to roomtemperature over 2 h followed by 40 min at reflux. The reaction mixturewas treated with saturated sodium hydrogen carbonate solution (50 ml)and extracted with ether (3×100 ml). The combined extracts were dried(Na₂ SO₄) and concentrated in vacuo to leave an orange oil. Theunreacted starting material was removed by heating under reflux in 8Mhydrochloric acid (50 ml) for 2 h, followed by basifying to saturationwith sodium hydrogen carbonate and extraction with ether. The organicextract was dried (Na₂ SO₄) and concentrated in vacuo to leave an orangeoil, which was distilled in a Kugelrohr apparatus (b.p. 190°-210°C./0.2-0.5 mmHg) followed by column chromatography on silica gel elutingwith ether, to give the title compound (D6) as a pale yellow oil (2.50g, 36%).

DESCRIPTION 7 Ethyl 1-benzyl-1-azoniabicyclo[2.2.11hept-4-yl-carboxylatebromide (D7) ##STR15##

(±) 7-Benzyl-7-aza-2-oxaspiro[4,4]nonan-1-one (D6, 2.5 g, 0.012 mole)was treated with a saturated solution of hydrogen bromide in ethanol(150 ml) and the resulting solution allowed to stand at room temperaturefor 3.5 days. The solution was concentrated in vacuo and the residuebasified with saturated potassium carbonate solution, stirred for 10mins and then extracted with chloroform (3×50 ml). The combined extractswere dried (Na₂ SO₄) and concentrated in vacuo to give the titlecompound (D7) as a beige solid (3.40 g, 87%).

DESCRIPTION 8 Ethyl 1-azabicyclo[2.2.1]hept-4-yl-carboxylate (D8)##STR16##

Ethyl 1-benzyl-1-azoniabicyclo[2.2.1]hept-4-yl-carboxylate bromide (D7,15 g, 0.044 mole) in ethanol (250 ml) was hydrogenated over 10% Pd oncarbon (1 g). The reaction was then filtered through celite and thefiltrate concentrated in vacuo to yield the crystalline hydrobromide.The salt was partitioned between chloroform and saturated aqueouspotassium carbonate solution. The organic phase was separated, dried,concentrated in vacuo and distilled to give the title compound (D8) as acolourless oil (7.7 g, 68%), b.p. 203°-205° C./10 mmHg.

EXAMPLE 1 (±)5-(3-Fluoromethyl-1,2,4-oxadiazol-5-yl)-1azabicyclo[3.2.l]octane oxalatesalt (El) ##STR17##

A solution of (±) ethyl 1-azabicyclo[3.2.1]oct-5-yl-(-carboxylate (D3,2.0 g, 0.011 mole) in 8M hydrochloric acid (70 ml) was heated underreflux for 22 h, then concentrated in vacuo to leave a white solid. Thiswas treated with thionyl chloride (30 ml) and heated under reflux for2.5 h, then concentrated in vacuo to give a yellow solid, which wasdissolved in absolute chloroform (100 ml) and treated withfluoroacetamide oxime (D1, 1.1 g, 0.012 mole). The mixture was heatedunder reflux for 1h, allowed to cool, then treated with excess saturatedpotassium carbonate solution and extracted with chloroform (2×100 ml).The combined extracts were dried (Na₂ SO₄) and concentrated in vacuo togive a beige solid, which was suspended in dry toluene (100 ml) andheated under reflux for 30 minutes. The mixture was allowed to cool,then filtered and concentrated in vacuo. The residue was chromatographedon silica gel eluting with 0 to 10% methanol/chloroform to give a paleyellow oil, which was converted to its oxalate salt and recrystallisedfrom methanol/ether to give the title compound (El) as a white solid(290 mg, 9%) m.p. 110°-1130° C.

Oxalate:- ¹ H--NMR (d₆ --DMSO)δ1.80-1.95 (1H, m), 2.00-2.20 (3H, m),2.30-2.50 (2H, m), 3.15-3.30 (2H, m), 3.35-3.65 (4H, m), 5.63 (2H, d,J=46Hz)

Analysis - C₁₀ H₁₄ N₃ OF.C₂ H₂ O₄ requires C: 47.B5. H: 5.35, N: 13.95;found C: 47.95, H: 5.45, N: 13.85

EXAMPLE 2 (±)5-(3-Amino-1,2,4-oxadiazol-5-yl)-1-azabicyclo-[3.2.11octane (E2)##STR18##

To a solution of sodium (3.5 g, 0.15 mole) in anhydrous ethanol (300 ml)under an atmosphere of nitrogen was added with continuous stirringhydroxy-guanidine hemisulphate hemihydrate (11.6 g, 0.086 mole) andpowdered 4A molecular sieves (35 g) and the resulting slurry stirred atroom temperature for 15 min. To this was added (±) ethyl1-azabicyclo[3.2.1]oct-5-yl carboxylate (D3, 4 g, 0.0218 mole) and thereaction mixture heated under reflux for 5 h. The reaction mixture wasthen cooled and adjusted to pH 7 with glacial acetic acid, filtered andthe filtrate concentrated in vacuo to a gum. This residue waspartitioned between chloroform and saturated aqueous potassium carbonatesolution. The organic phase was separated, dried over anhydrous sodiumsulphate and concentrated in vacuo to a gum which rapidly crystallised.Recrystallisation from ethyl acetate/methanol 1:1 afforded the titlecompound (E2, 1.9 g, 45%) m.p. 197°-199° C. ¹ H NMR (d⁶ -- DMSO)δ1.5(1H, m), 1.7-2.25 (5H, m), 265-3.15 (6H, m) 5 85 (2H, s, NH₂) ¹³ C NMR(d⁶ --DMSO)δ 18.7 (CH₂). 33.3 (CH₂). 35.45 (CH₂), 42.7 (C), 51.6 (CH₂),53.6 (CH₂), 63.7 (CH₂), 168.3 (C), 180 9 (C).

EXAMPLE 3 (±)5-(3-Acetylamino-1,2,4-oxadiazol-5-yl)-1azabicyclo[3.2.11octane oxalatesalt (E3) ##STR19##

A solution of (±)5-(3-amino-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.2.1]octane (E2, 200 mg,0.001 mole) in acetic anhydride (10 ml) was heated under reflux for 1h.The solvent was then removed in vacuo and the residue partitionedbetween chloroform and aqueous potassium carbonate solution. The organicphase was separated, dried over sodium sulphate and concentrated invacuo to a gum. A solution of this in ether (20 ml) was treated withoxalic acid (100 mg) in methanol (1 ml) and the product whichcrystallised out recrystallised from methanol/ether to afford the titlecompound (E3, 80 mg, 25%). m.p. 177°-178° C.

Oxalate: ¹ H NMR (d⁶ --DMSO)δ2.0 (1H, m), 2.2 (3H, m), 2.25 (3H, s),2.55 (2H, m), 3.4 (2H, m), 3.7 (4H, m), 11.35 (1H, s, N-H)

¹³ C NMR (d⁶ --DMSO)δ16.5 (4--C2), 23.2 (C3), 31.5 and 31.67 (3--C2,6--C2), 42.6 (5-C), 49.7 and 51.3 and 58.8 (3×N--C2), 162.5 and 164.6and 167.7 and 178.5 (3' and 5'--C, (CO₂ H)₂, C=O).

EXAMPLE 4 4-(3-Amino-1,2,4-oxadiazol-5-yl)-1-azabicyclo 2.2.1]heptane(E4) ##STR20##

A stirred solution of sodium (950 mg, 0.041 mole) in dry ethanol (30 ml)at room temperature under nitrogen was treated with powdered 3Amolecular sieves (10 g), hydroxy-guanidine hemisulphate hemihydrate (3.2g, 0.024 mole) and ethyl 1-azabicyclo[2.2.1]hept-4-yl-carboxylate (D8,1.0 g, 0.0059 mole) and the mixture heated under reflux for 4 h. Thereaction mixture was allowed to cool to room temperature, then filteredand the filtrate concentrated in vacuo to leave a gum, which was treatedwith saturated potassium carbonate solution (30 ml) and extracted withchloroform (2×30 ml). The combined extracts were dried (Na₂ SO₄) andconcentrated in vacuo to give a gum, which was crystallised frommethanol/ether to give the title compound (E4) as a white solid (330 mg,31%) m.p. 225°-226° C.

¹ H NMR (CD₃ OD)δ1.72-1.85 (2H, m), 2.12-2.28 (2H, m), 2.70-2.87 (4H,m), 3.05-3.20 (2H, m). 13C NMR (CD₃ OD)δ35.2 (CH₂), 47.9 (C), 55.2(CH₂), 63.9 (CH₂), 169.0 (C), 179.7 (C).

EXAMPLE 54-(3-Fluoromethyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.11heptaneoxalate salt (E5) ##STR21##

Ethyl 1-azabicyclo[2.2.1]hept-4-ylcarboxylate (D8, 1.03 g, 0.0061 mole)was treated with 8M hydrochloric acid (70 ml) and the solution heatedunder reflux for 12 h. The solution was concentrated in vacuo to leave awhite solid, which was treated with thionyl chloride (50 ml) and heatedunder reflux for 4 h. The reaction mixture was concentrated in vacuo andthe residue dissolved in ethanol-free chloroform (60 ml), treated withfluoroacetamide oxime (D1, 780 mg, 0.0080 mole) and heated under refluxfor 3 h. The reaction mixture was basified with potassium carbonatesolution and extracted with chloroform (2×50 ml). The combined extractswere dried (Na₂ SO₄) and concentrated in vacuo to leave a beige solid,which was suspended in toluene (50 ml) and heated under reflux for 0.5h. The mixture was concentrated in vacuo and the residue partitionedbetween saturated potassium carbonate solution and ethyl acetate. Theorganic solution was separated, dried (Na₂ SO₄) and concentrated invacuo to leave a yellow oil, which was chromatographed on basic aluminaeluting with ether. The colourless oil obtained was converted to itsoxalate salt and recrystallised from methanol/ether to give the titlecompound (E5) as a white solid (180 mg, 10%) m.p. 174°-176° C. Oxalate:-¹ H NMR (d⁶ --DMSO)δ2.05-2.17 (2H, m), 2.28-2.45 (2H, m), 3.15-3.32 (2H,m), 3.35-3.52 (4H, m), 5.62 (2H, d, J=46 Hz).

BIOLOGICAL ACTIVITY Radio ligand Binding

Cerebral cortex from Hooded Lister rats (Olac, UK) is homogenised in 2.5vols ice-cold 50 mM tris buffer pH 7.7 (at 25° C.). After centrifugationat 25,000×g at 4° C. for 15 min the pellet is resuspended in 2.5 volsbuffer and the wash repeated 3 times more. The final resuspension is in2.5 volumes and the homogenates are stored in 1 ml aliquots at -20° C.

Incubations (total volume 2 ml) are prepared using the above buffer withthe addition of 2 mM magnesium 16 chloride in the 3H-Oxotremorine-M(3H-OXO--M) 17 experiments. For 3H-Quinuclidinyl Benzilate (3H-QNB), 1ml of stored membranes is diluted to 30 ml and 0.1 ml mixed with testcompound and 0.27 nM (c. 25,000 cpm) 0.3H-QNB (Amersham International).For 3H--OXO--M, 1 ml of membranes is diluted to 6 ml and 0.1 ml mixedwith test compound and 2nM (c. 250,000 cpm) 3H--OXO--M (New EnglandNuclear).

Non-specific binding of 3H--QNB is defined using 1 μM Atropine sulphate(2 μM Atropine) and of 3H--OXO--M using 10 μM Oxotremorine. Non-specificbinding values typically are 5% and 25% of total binding, respectively.Incubations are carried out at 37° C. for 30 min and the samplesfiltered using Whatman GF/B filters. (In the 3H--OXO--M experiments thefilters are presoaked for 30 min in 0.05% polyethylenimine in water).Filters are washed with 3×4 ml ice-cold buffer. Radioactivity isassessed using a Packard BPLD scintillation counter, 3 ml Pico-Fluor 30(Packard) as scintillant.

This test provides an indication of the muscarinic binding activity ofthe test compound. The results are obtained as IC₅₀ values (i.e. theconcentration which inhibits binding of the ligand by 50%) for thedisplacement of the muscarinic agonist 3H--OXO--M and the muscarinicantagonist 3H--QNB. The ratio IC₅₀ (3H--QNB)/IC₅₀ (3H--OXO--M) gives anindication of the agonist character of the compound. Agonists typicallyexhibit a large ratio; antagonists typically exhibit a ratio near tounity.

The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                      [.sup.3 H]-OXO-M                                                                         [.sup.3 H]-QNB                                       Compound      IC.sub.50 (nM)                                                                           IC.sub.50 (nM)                                       ______________________________________                                        E1            6.9         900                                                 E2            11.0       2000                                                 E4            32.5       2250                                                 E5            140.0      19500                                                ______________________________________                                    

We claim:
 1. A compound of formula (I) or a pharmaceutically acceptablesalt thereof: ##STR22## in which X represents a group ##STR23## whereinone of Y and Z represents nitrogen and the other represents CR where Ris selected from halogen, CN, OR¹, SR¹, N(R¹)₂, NHR¹, NHCOR¹, NHCOOCH₃,NHCOOC₂ H₅, NHNH₂, COR¹, COR², C₂₋₄ alkenyl, C₂₋₄ alkynyl or C₁₋₂ alkylsubstituted with OR¹, N(R¹)₂, SR¹, CO₂ R¹, CON(R¹)₂ or one or twohalogen atoms, in which R¹ is hydrogen or C₁₋₂ alkyl and R² is OR¹, NH₂or NHR¹ ; and each of p and q independently represents an integer of 2to
 4. 2. A compound according to claim 1 in which X represents a group##STR24## wherein Y is nitrogen and Z is CR where R is as defined inclaim
 1. 3. A compound according to claim 2 wherein R is selected fromNH₂, CH₂ F and NHCOCH₃.
 4. A compound according to claim 1 in which prepresents 2 and q represents 2 or
 3. 5. A compound selected from:(±)5-(3-fluoromethyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.2.1]octane; (±)5-(3-amino-I,2,4-oxadiazol-5-yl)-1-azabicyclo[3.2.1]octane; (±)5-(3-acetylamino-1,2,4-oxadiazol-5-yl)-1-azabicyclo[3.2.1]octane;4-(3-amino-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.1]heptane; and4-(3-fluoromethyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.1]heptane; or apharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, as defined in claim 1, and a pharmaceuticallyacceptable carrier.
 7. A method of treatment and/or prophylaxis ofdementia in mammals including humans, which comprises administering tothe sufferer an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, as defined in claim 1.